Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD

To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.Peer reviewe

The first hominin of Europe

The earliest hominin occupation of Europe is one of the most debated topics in palaeoanthropology. However, the purportedly oldest of the Early Pleistocene sites in Eurasia lack precise age control and contain stone tools rather than human fossil remains(1-5). Here we report the discovery of a human mandible associated with an assemblage of Mode 1 lithic tools and faunal remains bearing traces of hominin processing, in stratigraphic level TE9 at the site of the Sima del Elefante, Atapuerca, Spain(6-8). Level TE9 has been dated to the Early Pleistocene ( approximately 1.2 - 1.1 Myr), based on a combination of palaeomagnetism, cosmogenic nuclides and biostratigraphy. The Sima del Elefante site thus emerges as the oldest, most accurately dated record of human occupation in Europe, to our knowledge. The study of the human mandible suggests that the first settlement of Western Europe could be related to an early demographic expansion out of Africa. The new evidence, with previous findings in other Atapuerca sites ( level TD6 from Gran Dolina(9-13)), also suggests that a speciation event occurred in this extreme area of the Eurasian continent during the Early Pleistocene, initiating the hominin lineage represented by the TE9 and TD6 hominins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62855/1/nature06815.pd

New insights into the neolithisation process in southwest Europe according to spatial density analysis from calibrated radiocarbon dates

The agricultural way of life spreads throughout Europe via two main routes: the Danube corridor and the Mediterranean basin. Current archaeological literature describes the arrival to the Western Mediterranean as a rapid process which involves both demic and cultural models, and in this regard, the dispersal movement has been investigated using mathematical models, where the key factors are time and space. In this work, we have created a compilation of all available radiocarbon dates for the whole of Iberia, in order to draw a chronological series of maps to illustrate temporal and spatial patterns in the neolithisation process. The maps were prepared by calculating the calibrated 14C date probability density curves, as a proxy to show the spatial dynamics of the last hunter-gatherers and first farmers. Several scholars have pointed out problems linked with the variability of samples, such as the overrepresentation of some sites, the degree of regional research, the nature of the dated samples and above all the archaeological context, but we are confident that the selected dates, after applying some filters and statistical protocols, constitute a good way to approach settlement spatial patterns in Iberia at the time of the neolithisation process

CD56negCD16+NK cells are activated mature NK cells with impaired effector function during HIV-1 infection

BACKGROUND: A subset of CD3(neg)CD56(neg)CD16(+) Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations. RESULTS: Using CD7 as an additional NK cell marker, we found that CD3(neg)CD56(neg)CD16(+) cells are a heterogeneous population comprised of CD7(+) NK cells and CD7(neg) non-classical myeloid cells. CD7(+)CD56(neg)CD16(+) NK cells are significantly expanded in HIV-1 infection. CD7(+)CD56(neg)CD16(+) NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to CD7(+)CD56(+)CD16(+) NK cells. CD7(+)CD56(neg) NK cells in healthy donors produced minimal IFNγ following K562 target cell or IL-12 plus IL-18 stimulation; however, they degranulated in response to K562 stimulation similar to CD7(+)CD56(+) NK cells. HIV-1 infection resulted in reduced IFNγ secretion following K562 or cytokine stimulation by both NK cell subsets compared to healthy donors. Decreased granzyme B and perforin expression and increased expression of CD107a in the absence of stimulation, particularly in HIV-1-infected subjects, suggest that CD7(+)CD56(neg)CD16(+) NK cells may have recently engaged target cells. Furthermore, CD7(+)CD56(neg)CD16(+) NK cells have significantly increased expression of CD95, a marker of NK cell activation. CONCLUSIONS: Taken together, CD7(+)CD56(neg)CD16(+) NK cells are activated, mature NK cells that may have recently engaged target cells

The small mammals (insectivores, bats and rodents) from the Holocene site of Vallone Inferno (Scillato, Sicily)

The Vallone Inferno rock-shelter is an archeological site located at 770 m a.s.l. in the Madonie massif in Sicily. This massif is modeled into the Triassic and Oligocene sedimentary rocks of the Imerese Basin. Thearchaeological excavations conducted since 2008 have provided a long prehistoric and historic sequence from the Neolithic to the medieval period. From the four sedimentary complexes identified, only levels 3.4 to 3.1 from complex 3 and 4.2 from complex 4 have yielded small-mammal material. Level 4.2 is poor in remains and as yet without cultural ascription, though it has a radiocarbon age of 9450±50 years BP. Level 3.4 has yielded fragments of ceramic characteristic of the Middle Neolithic-Bronze Age period, with a radiocarbon age between 3948±35 and3244±42 years BP. Levels 3.3 to 3.1 have provided ceramic fragments ascribed to the Late Roman-Byzantine period, with a radiocarbon age between1332±26 and 1260±34 years BP.The small-mammal assemblages recovered from the sieving-washing of all the sediment from the excavation campaigns include a total of at least 14 taxa (three insectivores, four chiropterans and seven rodents). The materials from this locality provide the first mention in the fossil record of Sicily for Suncus etruscus, Muscardinus avellanarius, Eliomys quercinus and Rattus norvegicus, as well as the last occurrence for Arvicola amphibius. The scarcity of the remains recovered from stratigraphic levels 3.1, 3.2, 3.3 and 4.2 makes it difficult to undertake a palaeoenvironmental and palaeoclimatical interpretation of them. However, the richness in small mammal contents from level 3.4 allow us to show that this level is dominated by dry meadows and woodland areas with a temperature and precipitation range that lies within the current values for the surrounding area, coinciding with the dry and temperate phase detected previously by marine surveys and pollen and microcharcoal studies

Active percussion tools from the Oldowan site of Barranco León (Orce, Andalusia, Spain): The fundamental role of pounding activities in hominin lifeways

Dated to 1.4 Mya, the Barranco León site (Orce, Andalusia, Spain) is currently the oldest and richest late Lower Pleistocene stone tool assemblage discovered so far in Europe. Archeological and paleontological remains are found clearly associated in lacustrine deposits traversed by a small channel. This paper provides new data about the lithic assemblage from level D, focusing on the abundant active percussion implements that form a part of the highly divers set of limestone macro-tools unique to this assemblage. Morpho-technological and experimental analysis of these tools allows us to hypothesize about the kinds of activities that might have been carried out by hominins at this site. Experimental work allows us to define percussive trace morphologies and to identify new types of percussion tools in the collection, beyond those of classical, ellipsoidal morphology. Analysis of the stone surfaces used for active percussion demonstrates that, while some of the tools could have been used for stone knapping, other hammer morphologies are not well adapted for this kind of activity. The morphology of the tools and the type of percussion damage displayed on their active surfaces provide criteria with which to widen the activity range of the hominins that used them. This study of the percussion instruments from Barranco León contributes essential data with which to buttress the growing interest in the macro component of Oldowan stone toolkits African and Eurasian sites and their possible uses

Perikymata numbers and enamel extension rates in the incisors of three archaeological modern human populations from two caves located in Spain: Maltravieso Cave (Cáceres) and Mirador Cave (Burgos)

A number of authors have studied the variability of total perikymata counts on permanent incisors in different modern human populations, finding that some populations show a significantly lower number of perikymata than others. However, little is known about the overall variability of these traits in archaeological populations of modern humans. Our aim was to broaden the available data on total perikymata counts on incisors, and to further discuss enamel extension rate variability in modern human incisors. Our sample consisted of 15 incisors from three different archaeological populations belonging to the Holocene: two populations from Mirador Cave (Sierra de Atapuerca, Burgos) assigned to two different chronological periods, and a population from Maltravieso Cave (Cáceres). We refer to these populations as the MTV-MIR sample. Perikymata were counted from several images obtained using an environmental scanning electron microscope (ESEM). Our results suggest the total number of perikymata of the MTV-MIR incisors fall most comfortably within the distribution of counts reported for modern Europeans and Inuit rather than those representing southern African samples of incisors. Furthermore, the percentage of the perikymata numbers in the last five deciles into which the crowns were divided (the cervical half) did not show statistically significant differences when compared to the other modern human populations. This suggests that enamel extension rates among modern human incisors share a common pattern, which might differ from that present in other species. More data from other modern and archaeological sub-Saharan African samples are needed to test whether low perikymata counts are exclusive to the southern African group or are indeed truly representative of sub-Saharan African populations as a whole today and in the past

CD56negCD16+NK cells are activated mature NK cells with impaired effector function during HIV-1 infection.

A subset of CD3(neg)CD56(neg)CD16 + Natural Killer (NK) cells is highly expanded during chronic HIV-1 infection. The role of this subset in HIV-1 pathogenesis remains unclear. The lack of NK cell lineage-specific markers has complicated the study of minor NK cell subpopulations. Using CD7 as an additional NK cell marker, we found that CD3(neg)CD56(neg)CD16 + cells are a heterogeneous population comprised of CD7 + NK cells and CD7(neg) non-classical myeloid cells. CD7 + CD56(neg)CD16 + NK cells are significantly expanded in HIV-1 infection. CD7 + CD56(neg)CD16 + NK cells are mature and express KIRs, the C-type lectin-like receptors NKG2A and NKG2C, and natural cytotoxicity receptors similar to CD7 + CD56 + CD16 + NK cells. CD7 + CD56(neg) NK cells in healthy donors produced minimal IFNγ following K562 target cell or IL-12 plus IL-18 stimulation; however, they degranulated in response to K562 stimulation similar to CD7 + CD56 + NK cells. HIV-1 infection resulted in reduced IFNγ secretion following K562 or cytokine stimulation by both NK cell subsets compared to healthy donors. Decreased granzyme B and perforin expression and increased expression of CD107a in the absence of stimulation, particularly in HIV-1-infected subjects, suggest that CD7 + CD56(neg)CD16 + NK cells may have recently engaged target cells. Furthermore, CD7 + CD56(neg)CD16 + NK cells have significantly increased expression of CD95, a marker of NK cell activation. Taken together, CD7 + CD56(neg)CD16 + NK cells are activated, mature NK cells that may have recently engaged target cells